Complement receptors CD21/CD35 provide an important link between innate and adaptive immunity by mediating the enhancing effects of complement on B cell activation and memory. On B cells they form a co-receptor along with CD19 and Tapa-1; whereas on FDC they provide a mechanism for antigen retention. In both cases they serve to enhance the effects of antigen on the humoral response. The overall goal of this proposal is to dissect the individual roles in vivo of the receptors in B cell activation, formation of germinal centers (GC) and maintenance of long-term memory. The approach is to use genetic models of mice deficient in complement receptors; construct mice that express mutant forms of the receptors or express antigen and activated complement on follicular dendritic cells to address the following three aims. (1) Test the hypothesis that co-receptor signaling is critical for B cell activation and survival within the lymphoid follicles and GC. (2) Test the hypothesis that complement-dependent retention of antigen on FDC is required for long-term persistence of antibody production and affinity maturation. (3) Test the hypothesis that complement-dependent antigen retention on FDC is required for maintenance of long-term memory B cells and their response to challenge. The significance of the proposal is that it addresses a fundamental problem in immunology, i.e. regulation of B-lymphocytes and their development into long-lived effector and memory B cells. An improved understanding of how B cells are regulated will lead to therapeutic approaches for manipulating the humoral response such as improved vaccines or inhibitors of chronic B cells responses.